Data from FDA - Curated by EPG Health - Last updated 15 June 2018

Indication(s)

INDICATIONS AND USAGE Women Gonal-f® (follitropin alfa for injection) is indicated for the induction of ovulation and pregnancy in the anovulatory infertile patient in whom the cause of infertility is functional and not due to primary ovarian failure. Gonal-f® is also indicated for the development of multiple follicles in the ovulatory patient participating in an Assisted Reproductive Technology (ART) program. Selection of Patients Before treatment with Gonal-f® is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Gonal-f® only if enrolled in an in vitro fertilization program. Primary ovarian failure should be excluded by the determination of gonadotropin levels. Appropriate evaluation should be performed to exclude pregnancy. Patients in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting Gonal-f® therapy. Evaluation of the partner's fertility potential should be included in the initial evaluation. Men Gonal-f® (follitropin alfa for injection) is indicated for the induction of spermatogenesis in men with primary and secondary hypogonadotropic hypogonadism in whom the cause of infertility is not due to primary testicular failure. Selection of Patients Before treatment with Gonal-f® is instituted for azoospermia, a thorough medical and endocrinologic evaluation must be performed. Hypogonadotropic hypogonadism should be confirmed, and primary testicular failure should be excluded by the determination of gonadotropin levels. Prior to Gonal-f® therapy for azoospermia in patients with hypogonadotropic hypogonadism, serum testosterone levels should be normalized.

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Advisory information

contraindications
CONTRAINDICATIONS Gonal-f® (follitropin alfa for injection) is contraindicated in women and men who exhibit: Prior hypersensitivity to recombinant FSH preparations or one of their excipients. High levels of FSH indicating primary gonadal failure. Uncontrolled thyroid or adrenal dysfunction. Sex hormone dependent tumors of the reproductive tract and accessory organs. An organic intracranial lesion such as a pituitary tumor. And in women who exhibit: Abnormal uterine bleeding of undetermined origin (see "Selection of Patients"). Ovarian cyst or enlargement of undetermined origin (see "Selection of Patients"). Pregnancy.
Special warnings and precautions
PRECAUTIONS General Careful attention should be given to the diagnosis of infertility in candidates for Gonal-f® (follitropin alfa for injection) therapy (see "Indications and Usage/ Selection of Patients"). Information for Patients Prior to therapy with Gonal-f®, patients should be informed of the duration of treatment and monitoring of their condition that will be required. The risks of ovarian hyperstimulation syndrome and multiple births in women (see " WARNINGS ") and other possible adverse reactions (see " Adverse Reactions ") should also be discussed. A 'Patient's Information Leaflet' is provided for patients prescribed Gonal-f® Multi-Dose. Laboratory Tests In most instances, treatment of women with Gonal-f® results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because plasma estrogens do not give an indication of the size or number of follicles. The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows: A rise in basal body temperature; Increase in serum progesterone; and Menstruation following a shift in basal body temperature. When used in conjunction with the indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following: Fluid in the cul-de-sac; Ovarian stigmata; Collapsed follicle; and Secretory endometrium. Accurate interpretation of the indices of follicle development and maturation require a physician who is experienced in the interpretation of these tests. Drug Interactions No drug/drug interaction studies have been performed. Carcinogenesis, Mutagenesis, Impairment of Fertility Long- term studies in animals have not been performed to evaluate the carcinogenic potential of Gonal-f®. However, follitropin alfa showed no mutagenic activity in a series of tests performed to evaluate its potential genetic toxicity including, bacterial and mammalian cell mutation tests, a chromosomal aberration test and a micronucleus test. Impaired fertility has been reported in rats, exposed to pharmacological doses of follitropin alfa (≥40 IU/kg/day) for extended periods, through reduced fecundity. Pregnancy See CONTRAINDICATIONS. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Gonal-f®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established.
Adverse reactions
ADVERSE REACTIONS Women The safety of Gonal-f® was examined in four clinical studies that enrolled 691 patients into two studies for ovulation induction (454 patients) and two studies for ART (237 patients). Adverse events occurring in more than 10% of patients were headache, ovarian cyst, nausea, and upper respiratory tract infection in the U.S. ovulation induction study and headache in the U.S. ART study. Adverse events (without regard to causality assessment) occurring in at least 2% of patients are listed in Table 13 and Table 14. Table 13: US Controlled Trial in Ovulation Induction, Study 5727 Body System Preferred Term Gonal-f® Patients (%) Experiencing Events Treatment cycles = 288up to 3 cycles of therapy n=118 Urofollitropin Patients (%) Experiencing Events Treatment cycles = 277 n= 114 Reproductive, Female Intermenstrual Bleeding 9.3% 4.4% Breast Pain Female 4.2% 6.1% Ovarian HyperstimulationSevere = 0.8% of 118 patients in Study 5727 6.8% 3.5% Dysmenorrhea 2.5% 6.1% Ovarian Disorder 1.7% 2.6% Cervix Lesion 2.5% 0.9% Menstrual Disorder 2.5% 0.9% Gastro-intestinal System Abdominal Pain 9.3% 12.3% Nausea 13.6% 3.5% Flatulence 6.8% 8.8% Diarrhea 7.6% 3.5% Vomiting 2.5% 2.6% Dyspepsia 1.7% 3.5% Central and Peripheral Nervous System Headache 22.0% 20.2% Dizziness 2.5% 0.0% Neoplasm Ovarian Cyst 15.3% 28.9% Body as a Whole- General Pain 5.9% 6.1% Back Pain 5.1% 1.8% Influenza-like Symptoms 4.2% 2.6% Fever 4.2% 1.8% Respiratory System Upper Respiratory Tract Infection 11.9% 7.9% Sinusitis 5.1% 5.3% Pharyngitis 2.5% 3.5% Coughing 1.7% 2.6% Rhinitis 0.8% 2.6% Skin and Appendages Acne 4.2% 2.6% Psychiatric Emotional Lability 5.1% 2.6% Urinary System Urinary Tract Infection 1.7% 4.4% Resistance Mechanism Moniliasis Genital 2.5% 0.9% Application Site Injection Site Pain 2.5% 0.9% Additional adverse events not listed in Table 13 that occurred in 1 to 2% of Gonal-f® treated patients in the US ovulation induction study included the following: leukorrhea, vaginal hemorrhage, migraine, fatigue, asthma, nervousness, somnolence, and hypotension. Table 14: US Controlled Trial in ART, Study 5533 Body System Preferred Term Gonal-f® Patients (%) Experiencing Events n=59 Urofollitropin Patients (%) Experiencing Events n= 61 Reproductive, Female Intermenstrual Bleeding 3.6% 5.2% Leukorrhea 1.7% 3.4% Vaginal Hemorrhage 3.6% 3.4% Gastro-intestinal System Nausea 5.4% 1.7% Flatulence 3.6% 0.0% Central and Peripheral Nervous System Headache 12.5% 3.4% Body as a Whole- General Abdominal Pain 8.9% 3.4% Pelvic Pain Female 7.1% 1.7% Respiratory System Upper Respiratory Tract Infection 3.6% 1.7% Metabolic and Nutritional Weight Increase 3.6% 0.0% Additional adverse events not listed in Table 14 that occurred in 1 to 2% of Gonal-f® treated patients in the U.S. Assisted Reproductive Technology (ART) study included the following: D&C following delivery or abortion, dysmenorrhea, vaginal hemorrhage, diarrhea, tooth disorder, vomiting, dizziness, paraesthesia, abdomen enlarged, chest pain, fatigue, dyspnea, anorexia, anxiety, somnolence, injection site inflammation, injection site reaction, pruritus, pruritus genital, myalgia, thirst, and palpitation. Two additional clinical studies (for ovulation induction and ART, respectively) were conducted in Europe. The safety profiles from these two studies were comparable to that of the data presented above. Gonal-f® Multi-Dose was examined in twenty-five healthy volunteers who received 300 IU each of Gonal-f® from single- dose ampules and multi-dose vials. Overall, both presentations were well tolerated and local tolerability between the two groups was comparable. Injection site inspections revealed very rare local reactions (mild redness in one patient after single-dose injection and mild bruising in two subjects after multi-dose injection). Subjective assessments indicated minimal or mild transient pain in two and five subjects who received Gonal-f® single-dose and Gonal-f® multi-dose, respectively. The following medical events have been reported subsequent to pregnancies resulting from gonadotropins in controlled clinical studies: Spontaneous Abortion Ectopic Pregnancy Premature Labor Postpartum Fever Congenital Abnormalities Two incidents of congenital cardiac malformations have been reported in children born following pregnancies resulting from treatment with Gonal-f® and hCG in Gonal-f® clinical studies 5642 and 5727. In addition, a pregnancy occurring in study 5533 following treatment with Gonal-f® and hCG was complicated by apparent failure of intrauterine growth and terminated for a suspected syndrome of congenital abnormalities. No specific diagnosis was made. The incidence does not exceed that found in the general population. The following adverse reactions have been previously reported during menotropin therapy: Pulmonary and vascular complications (see "Warnings"), Adnexal torsion (as a complication of ovarian enlargement), Mild to moderate ovarian enlargement, Hemoperitoneum There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established. Men The safety of Gonal-f® was examined in 3 clinical studies that enrolled 72 patients for induction of spermatogenesis and fertility of whom 56 patients received Gonal-f®. One hundred and twenty-three adverse events, including 7 serious events, were reported in 34 of the 56 patients during Gonal-f® treatment. In Study 5844, 21 adverse events, including 4 serious adverse events, were reported by 14 of the 26 patients (53.8%) treated with Gonal-f®. Events occurring in more than one patient were varicocele (4) and injection site reactions (4). The 4 serious adverse events were testicular surgery for cryptorchidism, which existed prestudy, hemoptysis, an infected pilonidal cyst, and lymphadenopathy associated with an Epstein-Barr viral infection. In Study 6410, 3 adverse events were reported in 2 of the 8 patients (24%) treated with Gonal-f®. One serious adverse event was reported, surgery for gynecomastia which existed at baseline. In the interim analysis of Study 6793, 18 of 22 patients (81.8%) reported a total of 99 adverse events during Gonal-f® treatment. The most common events of possible, probable, or definite relationship to study drug therapy occurring in more than 2 patients were: acne (25 events in 13 patients; 59% of patients); breast pain (4 events in 3 patients; 13.6% of patients); and fatigue, gynecomastia, and injection site pain (each of which was reported as 2 events by 2 patients; 9.1% of patients). Two serious adverse events (hospitalization for drug abuse and depression) were reported by a single patient in the interim analysis. A total of 12,026 injections of Gonal-f® were administered by the 56 patients who received Gonal-f® in Studies 5844, 6410, and 6793 combined. The injections were well-tolerated, with no or mild reactions (redness, swelling, bruising and itching) reported by patients for 93.3% of injections. Moderate and severe reactions, consisting primarily of pain, were reported for 4.8% of injections, and no self-assessment was available for 1.9% of injections. Postmarketing Experience In addition to adverse events reported from clinical trials, the following events have been reported during postmarketing use of Gonal-f®. Because these reactions were reported voluntarily from a population of uncertain size, the frequency or a causal relationship to Gonal-f®, can not be reliably determined. Body as a Whole - General: hypersensitivity reactions including anaphylactoid reactions Respiratory System: asthma (see Warnings, Pulmonary and Vascular Complications ) Vascular disorders: thromboembolism (see Warnings, Pulmonary and Vascular Complications )

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION Each Gonal-f® Multi-Dose Vial delivers 450 IU or 1050 IU follitropin alfa, respectively. Dosage Infertile Patients with oligo-anovulation The dose of Gonal-f® (follitropin alfa for injection) to stimulate development of the follicle must be individualized for each patient. The lowest dose consistent with the expectation of good results should be used. Over the course of treatment, doses of Gonal-f® may range up to 300 IU per day depending on the individual patient response. Gonal-f® should be administered until adequate follicular development is indicated by serum estradiol and vaginal ultrasonography. A response is generally evident after 5 to 7 days. Subsequent monitoring intervals should be based on individual patient response. It is recommended that the initial dose of the first cycle be 75 IU of Gonal-f® per day, ADMINISTERED SUBCUTANEOUSLY. An incremental adjustment in dose of up to 37.5 IU may be considered after 14 days. Further dose increases of the same magnitude could be made, if necessary, every seven days. Treatment duration should not exceed 35 days unless an E2 rise indicates imminent follicular development. To complete follicular development and effect ovulation in the absence of an endogenous LH surge, chorionic gonadotropin, hCG, (5,000 USP units) should be given 1 day after the last dose of Gonal-f®. Chorionic gonadotropin should be withheld if the serum estradiol is greater than 2,000 pg/mL. If the ovaries are abnormally enlarged or abdominal pain occurs, Gonal-f® treatment should be discontinued, hCG should not be administered, and the patient should be advised not to have intercourse; this may reduce the chance of development of the Ovarian Hyperstimulation Syndrome and, should spontaneous ovulation occur, reduce the chance of multiple gestation. A follow-up visit should be conducted in the luteal phase. The initial dose administered in the subsequent cycles should be individualized for each patient based on her response in the preceding cycle. Doses larger than 300 IU of FSH per day are not routinely recommended. As in the initial cycle, 5,000 USP units of hCG must be given 1 day after the last dose of Gonal-f® to complete follicular development and induce ovulation. The precautions described above should be followed to minimize the chance of development of the Ovarian Hyperstimulation Syndrome. The couple should be encouraged to have intercourse daily, beginning on the day prior to the administration of hCG until ovulation becomes apparent from the indices employed for the determination of progestational activity. Care should be taken to ensure insemination. In light of the indices and parameters mentioned, it should become obvious that, unless a physician is willing to devote considerable time to these patients and be familiar with and conduct the necessary laboratory studies, he/she should not use Gonal-f®. Assisted Reproductive Technologies As in the treatment of patients with oligo-anovulatory infertility, the dose of Gonal-f® to stimulate development of the follicle must be individualized for each patient. For Assisted Reproductive Technologies, therapy with Gonal-f® should be initiated in the early follicular phase (cycle day 2 or 3) at a dose of 150 IU per day, until sufficient follicular development is attained. In most cases, therapy should not exceed ten days. In patients undergoing ART, whose endogenous gonadotropin levels are suppressed, Gonal-f® should be initiated at a dose of 225 IU per day. Treatment should be continued until adequate follicular development is indicated as determined by ultrasound in combination with measurement of serum estradiol levels. Adjustments to dose may be considered after five days based on the patient's response; subsequently dosage should be adjusted no more frequently than every 3-5 days and by no more than 75-150 IU additionally at each adjustment. Doses greater than 450 IU per day are not recommended. Once adequate follicular development is evident, hCG (5,000 to 10,000 USP units) should be administered to induce final follicular maturation in preparation for oocyte retrieval. The administration of hCG must be withheld in cases where the ovaries are abnormally enlarged on the last day of therapy. This should reduce the chance of developing OHSS. Male Patients with Hypogonadotropic Hypogonadism The dose of Gonal-f® (follitropin alfa for injection) to induce spermatogenesis must be individualized for each patient. Gonal-f® must be given in conjunction with hCG. Prior to concomitant therapy with Gonal-f® and hCG, pretreatment with hCG alone (1,000 to 2,250 USP units two to three times per week) is required. Treatment should continue for a period sufficient to achieve serum testosterone levels within the normal range. Such pretreatment may require 3 to 6 months and the dose of hCG may need to be increased to achieve normal serum testosterone levels. After normal serum testosterone levels are reached, the recommended dose of Gonal-f® is 150 IU administered subcutaneously three times a week and the recommended dose of hCG is 1,000 USP units (or the dose required to maintain serum testosterone levels within the normal range) three times a week. The lowest dose of Gonal-f® which induces spermatogenesis should be utilized. If azoospermia persists, the dose of Gonal-f® may be increased to a maximum dose of 300 IU three times per week. Gonal-f® may need to be administered for up to 18 months to achieve adequate spermatogenesis. Administration Multi-Dose 450 IU Vial Dissolve the contents of one Multi-Dose vial (450 IU) with 1 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP. Resulting concentration will be 600 IU/mL. Following reconstitution as directed, product will deliver the equivalent of six 75 IU doses. Multi-Dose 1050 IU Vial Dissolve the contents of one Multi-Dose vial (1050 IU) with 2 mL Bacteriostatic Water for Injection (0.9% benzyl alcohol), USP. Resulting concentration will be 600 IU/mL. Following reconstitution as directed, product will deliver the equivalent of fourteen 75 IU doses. Patients should be instructed to use the accompanying syringes, calibrated in FSH units (IU FSH) for administration. The 27-gauge injection syringe (see figure below) has unit dose markings from 37.5 IU to 600 IU FSH for use with Gonal-f® Multi-Dose. Patients should be instructed to take a specific dose of Gonal-f® Multi-Dose. The doctor, nurse, or pharmacist should show the patient how to locate the syringe marking that corresponds to the prescribed dose. Figure 1 Patient Instructions for Use for Gonal-f® Multi-Dose Vial Step 1: Mixing (reconstituting) Gonal-f® Multi-Dose Vial Wash your hands with soap and water. Using your thumb, flip off the plastic cap of the Gonal-f® Multi-Dose vial. Wipe the top of the vial stopper with an alcohol swab. Carefully twist the needle cap off the syringe labeled 'Bacteriostatic Water for Injection, USP'. Do not touch the needle or allow the needle to touch any surface. Position the needle of the syringe of water in a straight, upright position over the marked center circle of the rubber stopper on the vial of Gonal-f® Multi-Dose powder. Keep the needle in a straight, upright position as you insert it through the center circle, or it may be difficult to depress the plunger. Slowly inject the water into the vial by depressing the syringe plunger. When all the water has been injected into the vial, withdraw the needle and safely dispose of it immediately in your needle container. Do not use this needle to inject your dose. Do not shake the vial. If bubbles appear, wait a few moments for the bubbles to settle. The liquid drug should be clear. Step 2: Preparing the Dose Wipe the rubber stopper of the vial of Gonal-f® Multi-Dose liquid with an alcohol wipe. Carefully pull the cap from the needle. Do not touch the needle or allow the needle to touch any surface. Firmly hold the vial of Gonal-f® Multi-Dose liquid on a flat surface, insert the needle through the marked center circle of the rubber stopper. Keeping the needle in the vial, lift the vial and turn it upside down with the needle pointing toward the ceiling. With the needle tip in the liquid, slowly pull back the plunger until the syringe fills to slightly more than the mark for your prescribed dose. Next, keeping the needle in the vial, slowly adjust the plunger to your prescribed dose – this will clear away any air bubbles. Check that you have the plunger set at your prescribed dose. Remove the syringe needle from the vial. Inject the prescribed dose as directed by the doctor. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Pregnancy and lactation
Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Gonal-f®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

Drug-Drug Interactions No drug-drug interaction studies have been conducted (see PRECAUTIONS).

More information

Category Value
Authorisation number NDA020378
Orphan designation No
Product NDC 44087-9070,44087-9030
Date Last Revised 23-05-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder EMD Serono, Inc.